The present invention generally concerns a method and apparatus for the electrically assisted delivery of a therapeutic agent (e.g., a drug) through a body surface (e.g., skin) at increased efficiency. This invention is particularly applicable to the electrotransport of highly potent therapeutic agents which are to be delivered at small dosage levels.
The present invention concerns in vivo methods and apparatuses for electrotransport delivery of therapeutic agents, typically drugs, into a patient. Herein the terms xe2x80x9celectrotransportxe2x80x9d, xe2x80x9ciontophoresisxe2x80x9d and xe2x80x9ciontophoreticxe2x80x9d are used to refer to methods and apparatus for transdermal delivery of therapeutic agents, whether charged or uncharged, by means of an applied electromotive force to an agent-containing reservoir. The particular therapeutic agent to be delivered may be completely charged (i.e., 100% ionized), completely uncharged, or partly charged and partly neutral. The therapeutic agent or species may be delivered by electromigration, electroosmosis or a combination of these processes. Electroosmosis has also been referred to as electrohydrokinesis, electro-convection, and electrically-induced osmosis. In general, electroosmosis of a therapeutic species into a tissue results from the migration of solvent, in which the species is contained, as a result of the application of electromotive force to a reservoir containing the therapeutic species.
As used herein, the terms xe2x80x9celectrotransportxe2x80x9d, xe2x80x9ciontophoresisxe2x80x9d and xe2x80x9ciontophoreticxe2x80x9d refer to (1) the delivery of charged drugs or agents by electromigration, (2) the delivery of uncharged drugs or agents by the process of electroosmosis, (3) the delivery of species by transport processes which include an electroporation step (See, e.g., Weaver et al U.S. Pat. No. 5,019,034), (4) the delivery of charged drugs or agents by the combined processes of electromigration and electroosmosis, and/or (5) the delivery of a mixture of charged and uncharged drugs or agents by the combined processes of electromigration and electroosmosis, combinations of the above processes to deliver either or both of charged or uncharged species.
Iontophoretic devices for delivering ionized drugs through the skin have been known since the early 1900""s. See for example Deutsch U.S. Pat. No. 410,009. In presently known electrotransport devices, at least two electrodes or electrode assemblies are used. Both electrodes/electrode assemblies are disposed so as to be in intimate electrical contact with some portion of the skin of the body. One electrode, called the active or donor electrode, is the electrode from which the ionic substance, agent, medicament, drug precursor or drug is delivered into the body through the skin by iontophoresis. The other electrode, called the counter or return electrode, serves to close the electrical circuit through the body. In conjunction with the patient""s skin contacted by the electrodes, the circuit is completed by connection of the electrodes to a source of electrical energy, e.g., a battery. For example, if the ionic substance to be delivered into the body is positively charged, then the positive electrode (the anode) will be the active electrode and the negative electrode (the cathode) will serve to complete the circuit. If the ionic substance to be delivered is negatively charged, then the cathodic electrode will be the active electrode and the anodic electrode will be the counter electrode.
As is discussed above, electrotransport delivery devices can be used to deliver uncharged drugs or agents into the body, e.g., transdermally. This is accomplished by a process called electroosmosis. Electroosmosis is the (e.g., transdermal) flux of a liquid solvent (e.g., the liquid solvent containing the uncharged drug or agent) which is induced by the presence of an electric field imposed across the skin by the donor electrode.
Electrotransport electrode assemblies/devices generally include a reservoir or source of the beneficial agent or drug (preferably an ionized or ionizable species or a precursor of such species), which is to be delivered into the body by electrotransport. Examples of such reservoirs or sources include a pouch as described in Jacobsen U.S. Pat. No. 4,250,878, a pre-formed gel body as disclosed in Webster U.S. Pat. No. 4,383,529 and Ariura, et al U.S. Pat. No. 4,474,570 and a receptacle containing a liquid solution as disclosed in Sanderson, et al U.S. Pat. No. 4,722,726. Such drug reservoirs are connected to the anode or the cathode of an electrotransport device to provide a fixed or renewable source of one or more desired species or agents. Electrical current is typically applied to the reservoir by means of a current distributing member, which may take the form of a metal plate, a foil layer, a conductive screen, or a polymer film loaded with an electrically conductive filler such as silver or carbon particles. The current distributing member, including any appropriate connectors and associated connective conductors such as leads, and the reservoir comprise an electrode assembly herein.
The prior art has recognized that xe2x80x9ccompetitivexe2x80x9d ionic species having the same charge (i.e., the same sign) as the drug ions being delivered by electrotransport have a negative impact on electrotransport drug delivery efficiency. The efficiency (E) of electrotransport delivery of a particular species is defined herein as the rate of electrotransport delivery of that species per unit of applied electrotransport current (mg/mA-h). The prior art further recognized that competitive ionic species were inherently produced during operation of these devices. The competitive species produced are dependent upon the type of electrode material which is in contact with the drug solution. For example, if the electrode is composed of an electrochemically inert material (e.g., platinum or stainless steel), the electrochemical charge transfer reaction occurring at the electrode surface tended to be water electrolysis since water is the overwhelmingly preferred liquid solvent used in electrotransport drug solutions. Water electrolysis produces competing hydronium ions at the anode (in the case of cationic electrotransport drug delivery) and competing hydroxyl ions at the cathode (in the case of anionic electrotransport drug delivery). On the other hand, if the electrode is composed of an electrochemically oxidizable or reducible species, then the electrode itself is oxidized or reduced to form a competitive ionic species. For example, Untereker et al U.S. Pat. No. 5,135,477 and Petelenz et al U.S. Pat. No. 4,752,285 recognize that competitive ionic species are electrochemically generated at both the anode and cathode of an electrotransport delivery device. In the case of an electrotransport delivery device having a silver anodic donor electrode, application of current through the silver anode causes the silver to become oxidized (Agxe2x86x92Ag++exe2x88x92) thereby forming silver cations which compete with the cationic drug for delivery into the skin by electrotransport. The Untereker and Petelenz patents teach that providing a cationic drug in the form of a halide salt causes a chemical reaction which removes the xe2x80x9ccompetingxe2x80x9d silver ions from the donor solution (i.e., by reacting the silver ions with the halide counter ion of the drug to form a water insoluble silver halide precipitate; Ag++Xxe2x88x92xe2x86x92AgX), thereby achieving higher drug delivery efficiency. In addition to these patents, Phipps et al PCT/US95/04497 filed on Apr. 7, 1995 teaches the use of supplementary chloride ion sources in the form of high molecular weight chloride resins in the donor reservoir of a transdermal electrotransport delivery device. These resins are highly effective at providing sufficient chloride for preventing silver ion migration, yet because of the high molecular weight of the resin cation, the resin cation is effectively immobile and hence cannot compete with the drug cation for delivery into the body.
The prior art has long recognized that the application of electric current through skin causes the electrical resistance of the skin to decrease. See, for example, Haak et al U.S. Pat. No. 5,374,242 (FIG. 3). Thus, as the electrical resistance of the skin drops, lower voltages are needed to drive a particular level of electrotransport current through the skin. This same phenomenon is observed in a technique referred to as xe2x80x9celectroporationxe2x80x9d of the skin. See Weaver et al U.S. Pat. No. 5,019,034. Electroporation involves the application of short, high voltage electrical pulses to produce what is characterized as a transient (e.g., decreasing to normal levels in 10 to 120 sec. for excised frog skin) increase in tissue permeability. Electroporation is also characterized by the creation of pores in lipid membranes due to reversible electrical breakdown. Electroporation does not, itself, deliver any drug but merely prepares the tissue thereby treated for delivery of drug by any of a number of techniques, one of which is iontophoresis.
The present invention arises from the discovery that when delivering a therapeutic agent (e.g., a drug) via electrotransport through a living body surface (e.g., skin) of an animal (e.g., a human) using a pulsing electrotransport current, the efficiency of electrotransport agent delivery is increased by maintaining the width of the applied current pulses above a minimum period of time. For certain drugs delivered transdermally to humans via electrotransport, this minimum period has been found to be about 5 msec, and preferably about 10 msec. In general, this discovery means that lower frequency pulsing electrotransport currents tend to provide more efficient agent delivery than higher frequency pulsing electrotransport currents, since the longer the pulse width, the fewer the number of pulses which can be applied in any unit of time. Thus, when using pulsing currents having pulse widths of at least about 5 msec, and preferably at least about 10 msec, the pulsing frequencies tend to be less than about 100 Hz and more preferably less than about 10 Hz.
As used herein, the term xe2x80x9celectrotransport agent delivery efficiency (E)xe2x80x9d means the rate of transdermal electrotransport delivery (mg/h) per unit of applied electrotransport current (mA) and expressed in units of micrograms of agent (i.e., drug) delivered per milliamp-hour of applied electric current (xcexcg/mAh). Electrotransport delivery efficiency, in some aspects of its meaning, is analogous to transport number. Transport number is a unitless quantity, less than one, indicating the fractional charge carried by a particular ionic species, e.g., a drug or agent, during electrotransport delivery. Electrotransport delivery efficiency, as defined herein, is more broadly applicable to include the transport of uncharged species and is more reflective of the scope of the invention.
The terms xe2x80x9cpulsing currentxe2x80x9d and xe2x80x9cpulsed currentxe2x80x9d as used herein refer to an applied electrotransport current having a periodic (i.e., the waveform repeats over time and has a wave length and a frequency) waveform shape comprised of a first segment of applied electrotransport current having a first average current magnitude, and a second segment of applied electrotransport current having a second average current magnitude, the second average current magnitude being less than the first average current magnitude. In general, the second average current magnitude is less than about 70% of the first average current magnitude, more typically less than about 50% of the first average current magnitude and most typically less than about 25% of the first average current magnitude. The second average current magnitude can be zero or substantially zero, but in any event is substantially less than the first average current magnitude.
The present invention is not limited to any particular periodic pulsed waveform shape and may take the form of any of various types of periodic waveforms including sinusoidal, trapezoidal, square or rectangular current waveforms. A square pulsed current waveform shape is particularly suitable for practicing this invention.
In a preferred embodiment of the present invention, the first average current magnitude is sufficient to produce a current density which is equal to or greater than a critical current density, Ic. Applied electrotransport current densities (generally expressed in units of microamperes per square centimeter (xcexcA/cm2) herein) above this critcal level result in even further enhancement of electrotransport transdermal agent delivery efficiency. This xe2x80x9cfurtherxe2x80x9d enhancement of the skin""s electrotransport delivery efficiency has been found to be non-transitory, i.e., to last for at least several minutes to several hours or longer after application of current densities and over periods of time in accordance with this preferred embodiment of the invention. This preferred embodiment of the invention induces (e.g., through a pre-treatment or pre-application step in which species are delivered) a high efficiency drug-transmissive state in the skin to which an electrotransport drug delivery device is applied. The induced, high efficiency state continues and can be utilized to deliver drug or other therapeutic agent transdermally with increased efficiency. In usual circumstances, this will permit delivery of drug with more precise control and at a lower current. This phenomenon has only been found in the transdermal delivery of drug or agent through intact living skin or tissue (i.e., in vivo) and is not exhibited in dead skin (i.e., excised skin Through which species are electrotransported in vitro). In this manner, the treated skin exhibits a statistically significant, non-transitory increase in drug delivery efficiency relative to skin which has not been so treated. Generally speaking, utilization of this preferred embodiment of the invention significantly increases the drug/agent delivery efficiency and reduces or eliminates variability in the drug delivery efficiency of the skin site which is so treated. Since electrotransport delivery efficiency remains elevated and less variable after utilization of this embodiment (relative to untreated skin), utilization of this embodiment of the invention permits the delivery of drug or agent through intact skin by electrotransport with increased control and efficiency.
Thus, in one aspect, the present invention is a method of electrotransport drug or agent delivery through a body surface involving the steps of delivering a therapeutic agent by a pulsing electrotransport current, the current pulses being sufficiently long (i.e., at least about 5 msec and preferably at least about 10 msec), to reduce or avoid capacitive loss and thereby deliver the agent at an enhanced electrotransport delivery efficiency (E). In a preferred aspect, the current pulses have a sufficient magnitude to produce a current density greater than or equal to Ic, to convert the electrotransport delivery efficiency of the body surface (i.e., the skin) through which the agent is delivered to a non-transitory state of higher electrotransport delivery efficiency. Thereafter, the drug or agent is delivered through the body surface while the body surface is in the higher efficiency transfer state.